The mechanisms that mediate tissue damage and fibrosis in sarcoidosis are poorly understood. The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have to be considered in this regard, since they control the lysis of connective tissue components. Immunohistochemical studies (peroxidase and dual labeling for confocal microscopy) of the reactivity for MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, membrane-type-1-MMP, (MT-1-MMP), MT-2-MMP, MT-3-MMP, MT-4-MMP, TIMP-1 and TIMP-2 were made on tissues from patients with cardiac (n=4) and pulmonary (n=5) sarcoidosis. The granulomas were histochemically similar in both organs. The multinucleated giant cells showed moderate reactivity for MMP-1 and MMP-9, and variable reactivity for MMP-2 and MMP-3; in addition, they showed colocalization of MT-1-MMP, which activates MMP-2. The reactivity of epithelioid cells was moderate for MMP-2 and mild for other MMPs. Macrophages showed weaker reactivity for MMPs than did multinucleated giant cells and epithelioid cells. All three types of cells showed very low reactivity for TIMPs. Staining for type IV collagen showed focal damage to the basement membranes of cardiac myocytes and pulmonary alveoli near the granulomas. The cells in sarcoid granulomas contain an abundance of MMPs and a paucity of TIMPs. The multinucleated giant cells also contain MT-1-MMP; therefore, they can activate MMP-2 in the granulomas. The MMPs can cause damage to adjacent cardiac myocytes and pulmonary alveoli, thereby leading to the interstitial fibrosis produced by sarcoidosis. - Sarcoidosis; matrix metalloproteinases; tissue inhibitors of matrix metalloproteinases; histochemistry; heart; lung.